This was considered

by many as a breakthrough that confirmed the utility of personalized medicine [23]; however, its utility is now being questioned. There has been a steady increase in the use of pharmacogenetic data to enhance risk/benefit ratios; the product inserts of over a dozen drugs now carry pharmacogenetic Selleckchem R428 information. However, progress is particularly lacking in the application of pharmacogenetics to the development and use of protein therapeutics [24]. It would be logical for drug development approaches to integrate pharmacogenetic information about both the protein-drug and its protein-target; nevertheless, given the complexity of biological systems, the selection of appropriate biomarkers and the study design remain daunting tasks. Can ns-SNPs in the F8 genes of HA patients be predictors (biomarkers) of potential immunogenicity of FVIII replacement proteins via the amino acid substitutions encoded in their endogenous (albeit non-functional or dysfunctional) FVIII proteins? Allelically mismatched ns-SNPs create structural differences between the endogenous and infused FVIII proteins that are comparable in scale to differences created MK-1775 in vivo by missense mutations, which comprise the most common type of HA-causing F8 abnormality. Although typically less than 5–10% of all HA patients

with missense mutations become alloimmunized to replacement products, this low incidence partly reflects the fact that patients with mild HA require treatment infrequently and that the use of DDAVP is preferred to FVIII infusions whenever possible. The HAMSTeRS (Haemophilia A Mutations, Structure, Test and Resource Site) database (http://hadb.org.uk/) [25] lists inhibitor development in 15–50% of subjects with five highly recurrent missense mutations (Arg593Cys, Tyr2105Cys, Arg2150His, Trp2229Cys, or Pro2300Leu) [26–29]. These recurrent mutations, together with greater than 50 non-recurrent or less frequently

recurring missense mutations identified in inhibitor patients, most of which are also reported in HAMSTeRS Fenbendazole (Fig. 1), provide evidence that wild-type FVIII proteins can be immunogenic even when infused in patients who express and circulate dysfunctional FVIII proteins with sequences that differ from the infused FVIII by as little as a single amino acid residue. Despite this knowledge, ns-SNPs are only now beginning to be rigorously sought and appropriately evaluated in studies of the FVIII immune response. In a recent study, four common ns-SNPs were identified in the F8 genes of a small number of healthy unrelated individuals from seven racial groups (Fig. 2a) [8]. The alleles of these ns-SNPs existed as six naturally occurring combinations (haplotypes) referred to as H1-H6 (Fig. 2b) [13]. Thus, these six haplotypic variations of F8– all of which are wild-type – were observed in the healthy male and female subjects studied.